This Program Project in Liver Diseases focuses on the following main areas: 1. Regulation of hepatic cholesterol metabolism with emphasis on factors that control cholesterol entry into bile. These studies are made possible by recent developments in this laboratory of new techniques that allow quantitation of (a) absolute rates of cholesterol synthesis in the liver and other tissues, and of (b) rates of receptor-dependent and receptor-dependent low density lipoprotein uptake into the liver, and the development of several animal models in which the output of cholesterol by the liver into bile can be systematically varied. It is anticipated that these studies will elucidate mechanisms responsible for secretion of excessive amounts of cholesterol into bile and thereby provide important insights into the pathogenesis of cholesterol gallstones. 2. The immunologic and metabolic function of hepatic simusoidal cells. The liver is a prominent site of antigen localization and contains a rich supply of candidate accessory cells, such as Kupffer cells and sinusoidal endothelial cells. Despite these characteristics, antigen entering the liver in vivo appears not to be immunogenic and may be tolerogenic. In contrast, we have demonstrated that Kupffer cells are capable of supporting mitogen and antigen-induced T lymphocyte proliferation in vitro. The proposed studies aimed at resolving this paradox have been made possible by the demonstration in this laboratory that sinusoidal endothelial cells can serve as accessory cells in immune responses, displaying both augmentative and suppressive characteristics whem mixed with Kupffer cells, and the development of a system for isolating and maintaining sinusoidal endothelial cells in long-term culture. Development of cell separation techniques will be adapted to human liver providing a means for assessing the immunologic function of human non-parenchymal cells. 3. Expertise in lipoprotein metabolism has spawned an important thrust on the immunomodulatory role of normal and abnormal lipoproteins. Development of liver cell isolation techniques is permitting an assessment of the contribution of parenchymal, Kupffer and endothelial cells to hepatic uptake of lipoproteins by receptor and non-receptor mediated pathways.